ES2305057T3 - DEVICE FOR THE ADMINISTRATION OF ORAL PHARMACES. - Google Patents

Abstract

A device for oral administration of a therapeutic agent for gastrointestinal deposition or sublingual or oral absorption, comprising a housing and an actuator and multiple doses of multiparticles comprising medicament particles, said device distributing after actuation a unit dose of said multiparticles, the unit dose being distributed from the device substantially by gravitational force and with an air flow of less than 20 liters / minute, in which said medicament particles have an average diameter greater than 10 mum to about 1 mm, so that An effective dose of said medication cannot be distributed to the lower lung of a human patient.

Description

Device for drug administration oral

Field of the invention

The present invention is directed to a device of distribution for oral administration of therapeutic agents in powder form for gastrointestinal deposition.

Background of the invention

The most prominent mode of distribution of therapeutic agents in orally by means of solid dosages such as tablets or capsules. The oral administration of solid dosage forms is more convenient and accepted than other modes of administration, by example, parenteral administration. However, manufacturing, dispensing and administration of solid dosage forms no They are without problems and associated inconveniences.

With the manufacture of dosage forms solid, in addition to the active agent, it is necessary to combine other ingredients in the formulations for several reasons, such as enhance the physical appearance, provide the necessary mass for the pastilles or capsules, improve stability, improve compressibility or help disintegration after administration. However, these added excipients have been shown to negatively influence release, stability and bioavailability of the active ingredient. Excipients Additives are a particular problem with medications that require a high dose in order to provide a therapeutic effect, for example, bisphosphonate medications. The excipient inclusion additional can make the final tablet extremely large, what which can result in esophageal damage due to physical characteristics of the dosage form if not swallowed properly. Esophageal damage can also be caused by toxicity produced by the medication itself, if the tablet stays in the throat or has a transit time increased through the esophagus due to its increased size.

In addition, the pastillation of certain medications It has many associated production problems. In particular, many medications, for example, acetaminophen, have bad compressibility and cannot be compressed directly in ways of solid dosage. Consequently, such medications must be or wet granules or manufactured in a special class with the so that they are pastillated, which increases the stages of Manufacturing and production costs.

Adherence to good manufacturing practices and process controls is essential in order to minimize the variations of dosage form to dosage form and of load to load of the final product. Even strict adherence to These practices are not yet a guarantee that there will be a acceptable variation.

With the high cost of scale production industrial and government approval of dosage forms solid, such formulations are often available in a number limited concentrations, which only satisfies the needs of the major sectors of the population. Unfortunately, this practice leaves many patients without means. acceptable treatment and doctors in a dilemma regarding to individualize the dosages to meet the needs Clinics of their patients.

The dispensing of dosage forms Oral solids also makes formulations susceptible to degradation and contamination due to repackaging, storage inappropriate and manual handling.

There are also many patients who are unable or unwilling to take conventional orally administered dosage forms. For some patients, the perception of the unacceptable oral taste or sensation of a dose of medicine leads to a reflex jaw action that makes swallowing difficult or impossible. Other patients, for example, pediatric and geriatric patients, find it difficult to ingest the typical solid oral dosage forms, for example, due to the size of the tablet. Other patients, particularly older patients, have health conditions such as achlorhydria that prevents the successful use of oral solid dosage forms. Aclorhydria is a state of health in which there is an abnormal deficiency or absence of free hydrochloric acid in the gastric secretions of the stomach. This state of health prevents the disintegration and / or dissolution of oral solid dosage forms, particularly dosage forms with high excipient payloads or
insoluble

Solutions / suspensions have been developed flavored of some therapeutic agents to facilitate the oral administration of oral agents to patients who have normally difficulty ingesting oral dosage forms conventional solids. Although liquid formulations are more easily administer to the patient with problems, the Liquid / suspension formulations are not free of their own significant problems and restrictions. The amount of dose liquid is not controlled so easily compared to the ways in tablet and capsule and many therapeutic agents are not sufficiently stable in the form of solution / suspension. Indeed, most suspension type formulations they are typically reconstituted by the pharmacist and therefore they have a limited shelf life, even under refrigerated conditions Another problem with the formulations liquids that is not so much a factor with tablets and capsules is The taste of the active agent. The taste of some agents therapeutic is so unacceptable that liquid formulations do not They are a viable option. In addition, type formulations solution / suspension are typically unacceptable where the agent active must be provided with a protective coating, for example, a coating that masks the taste or a coating enteric to protect the active agent from conditions Strongly acidic stomach.

Another alternative for dosage forms oral for certain medications are the dosage forms in aerosol that administer therapeutic agents by deposition in the pulmonary system The use of aerosol dosage forms has Many advantages for the patient. The active ingredient container It is convenient and easy to use, usually with manipulation limited manual. As the medicine is sealed inside the device, direct manipulation of the medication is eliminated and air and moisture content contamination can be Keep at a minimum. In addition, a valve can be included measured in the device in order to individualize the dose for private patients However, such formulations also have disadvantages, such as decreased bioavailability of medication due to inappropriate administration by the patient. For example, if a patient's breathing is not coordinated with the device activation, the active agent will not reach your site of intended action, which will lead to a decrease in the therapeutic benefit

Another alternative is the dosage forms dry powder For example, the International Patent Application WO 94/04133 describes a powder composition for inhalation that contains a microfine medication, such as salbutamol sulfate, and a support containing an antistatic agent. The support is calcium carbonate or a sugar, especially lactose. The amount Support is 95-99.99 percent by weight. It is said that that the compositions are useful for agent distribution active to the lungs while providing side effects reduced, such as nausea, maximizing its proportion of medicine that reaches the lungs.

U.S. Patent No. 4,590,206 describes capsules, cartridges or aerosol containers containing spray dried sodium cromoglycate in finely form divided and not agglomerated. A substantial proportion of individual drug particles have sizes and shapes that they allow deep penetration into the lung and yet they are fluids to allow filling of capsules.

WO International Patent Application 93/25198 is directed to an ultra-fine powder for inhalation. Dust comprises a medicament and hydroxypropylcellulose and / or hydroxypropyl methylcellulose. It is said that more than 80 percent in weight of the dust particles has a particle diameter of 0.5-10 micrometers It is said that dust is capable of reaching the lower trachea and bronchi.

WO International Patent Application 95/34337 describes a reusable inhaler and a medicated package, which uses a patient's breathing to extract the medication in powder of the inhaler and within the bronchial and lung area of the Username. It is said that the inhaler controls the flow rate of air inside the chamber and prevents the patient from blowing into the inhaler.

WO 96/23485 is related to the provision of a powder for use in dry powder inhalers that comprises active particles, support particles and material additive. The active particles have an aerodynamic diameter at the range of 0.1 to 5 µm. The purpose of the WO document 96/23485 is to create an improved dry powder composition ensuring that the active agent is in the form of particles of size inhalable (<10 µm) after device operation inhaler to increase the deposition in the lung.

Due to the disadvantages of the distribution of known medications discussed above (as well as other disadvantages) there is a need in the art for development of a device and method to facilitate the distribution of a wide range of therapeutic agents for gastrointestinal deposition and that minimizes lung deposition of materials that have undesirable or unknown pulmonary toxicology but that are approved for oral administration.

Objects of the invention

It is an object of the invention to create a system for the distribution of a dose of a therapeutic agent in the form of multiparticles for gastrointestinal deposition.

It is an object of the invention to create a system for oral administration of a dose of a therapeutic agent in the form of multiparticles in the oral cavity of a patient to gastrointestinal deposition

It is an object of the invention to create a system for dispensing a dose of a therapeutic agent in the form of multiparticles for subsequent administration in the cavity oral for gastrointestinal deposition.

It is another object of the invention to create a system for the distribution of multiple doses of a therapeutic agent in multi-particle form that minimizes the need for excipients inert pharmacists.

It is another object of the invention to create a system for the distribution of multiple doses of a therapeutic agent in Multi-particle form for quick release, standard, maintained, controlled or directed.

It is another object of the invention to create a system for the distribution of a dose of a therapeutic agent for gastrointestinal deposition that protects the active ingredient from pollution and humidity

It is another object of the invention to create a system for the distribution of a dose of a therapeutic agent for gastrointestinal deposition that allows the dosage to be adjustable based on the needs of an individual patient or patient population

It is another object of the invention to create a system for the distribution of a dose of a therapeutic agent for gastrointestinal deposition that can be used for a wide variety of agents for a wide variety of therapies, for for example, to treat systemic and / or local health states.

It is another object of the invention to create a system for the distribution of two or more different medications in the form of multiparticles simultaneously or at different times. He System device may contain the 2 or more medications in compartments separated or together in the same compartment.

It is another object of the invention to create a system for the distribution of a dose of a therapeutic agent for gastrointestinal deposition that provides variability acceptable from dose to dose and load to load.

It is another object of the invention to create a system for the distribution of a dose of a therapeutic agent for gastrointestinal deposition that can be administered and swallowed without Help of a fluid.

The foregoing objects of the invention and others are achieved by virtue of the present invention which, in certain embodiments, creates a drug distribution system for the distribution of a drug for gastrointestinal deposition. The system comprises a device for oral administration of a therapeutic agent for gastrointestinal deposition or sublingual or buccal absorption, comprising a housing and an actuator and multiple doses of multiparticles comprising drug particles, the device distributing in the drive a unit dose of the multiparticles, the unit dose being distributed from the device substantially by gravitational force and with an air flow of less than 20 liters / minute, in which the medicament particles have an average diameter greater than 10 µm to about 1 mm , so that an effective dose of the drug cannot be distributed in the lower lung of a human patient. The drug distribution system can be used to administer the unit dose of multiparticles in the patient's oral cavity ( in vivo ) or to dispense the unit dose into an intermediate receptacle ( ex-vivo ) for subsequent gastrointestinal deposition.

In certain embodiments, the invention creates a device for the distribution of a medicament comprising a housing and an actuator, the device being able to contain multiple doses of multiparticles comprising medicament particles, the device being capable of administering a unit dose. of the multiparticles, in which the multiparticles have an average diameter greater than 10 µm, and preferably less than about 1 mm, in order to minimize the pulmonary deposition of the multiparticles and so that an effective dose cannot be distributed of the medication in the lower lung of a human patient. The device can be used to administer the unit dose of multiparticles in the patient's oral cavity ( in-vivo ) or to dispense the unit dose into an intermediate receptacle ( ex-vivo ) for subsequent gastrointestinal deposition.

In certain embodiments, the invention creates a device for distributing multiple unit doses of a medication  in the form of multiparticles comprising a housing to contain the multiple dose multi-particle unit comprising medicament particles, the housing having an opening for distribute a unit dose of multiparticles; a component of operable measurement between a first position in which it receives a unit dose from said housing and a second position in which distributes the unit dose of medication to the opening in the Case; the unit dose being distributed from the device towards the outside of the device through the opening of the housing with an air flow of less than about 20 liters / min. In preferred embodiments, the device does not include a propellant to facilitate the distribution of the unit dose and preferably the unit dose is distributed through the opening substantially by gravitational force.

In certain embodiments, the invention creates a device to distribute multiple doses unit of medication in the form of multiparticles comprising a housing to contain the multiple dose multi-particle unit comprising medicament particles, the housing having a nozzle for distribute a unit dose of multiparticles in the cavity oral of a patient; means to separate a unit dose from multiparticles of the carcass and distribute the unit dose in the mouthpiece, the mouthpiece having a medication receiving end connected to the separation means and a distribution end of the medication through which the unit dose is distributed outside of the device, the nozzle being placed on the device so that the drug particles expelled through the mouthpiece can be deposited in a patient's oral cavity substantially no deposition of drug particles in the patient's lungs

In certain embodiments, the invention creates a device for distributing multiple unit doses of a medication  in the form of multiparticles comprising a housing to contain the multiple dose multi-particle unit comprising medication particles; the housing having a nozzle for distribute a unit dose of multiparticles in the cavity oral of a patient; a measurement component to separate a dose unit of the multiparticles of the housing and distribute the dose unit in the nozzle, the nozzle having a receiving end of the medicine connected to the measurement component and one end of distribution of the medication through which the unit dose is distributed outside the device, the nozzle being placed over the device so that the drug particles expelled through the nozzle can be deposited in the cavity oral of a patient substantially without particle deposition of medication in the patient's lungs.

A method to prepare a system of distribution of medication to distribute multiple doses of a medicine for gastrointestinal deposition comprises preparing a multiparticle drug formulation so to provide particles that, when placed in the oral cavity and swallowed, deposited in the gastrointestinal tract and not deposit in any substantial amount in the lungs; and place multiple unit doses of said medicament formulation in a device that measures a single unit dose for distribution.

In certain embodiments, a formulation of medicine for gastrointestinal deposition comprises a plurality of free flowing and uncompressed particles that comprise a drug and a pharmaceutically excipient acceptable, the particles having an average diameter greater than 10 um up to about 1 mm, the particles comprising less than 80% of medication, preferably at least About 90% of medication.

In certain embodiments, the formulation of medication may also comprise a facilitating agent (for example, an absorbability enhancer, a modifier of the texture, a taste masking agent, a sweetener, a flavoring, a salivary stimulator, an effervescent compound or their combinations) that increases the oral administrability of the unit dose.

In certain embodiments, the formulation of medication may further comprise a material to provide a quick release, standard, maintained, controlled or directed.

In certain embodiments of the invention, deposits greater than about 80% of the unit dose in the gastrointestinal tract, preferably deposited greater than about 90% or greater than about 95%, and most preferably about 100% of the unit dose in the tract gastrointestinal.

In the preferred embodiments of the invention, The unit dose comprises a discrete collection of multiparticles.  For the purposes of the invention, "a discrete collection" means that the multi-particles are in the form of a unit that flows freely, not compressed and not dispersed in a cloud or fog, which effectively minimizes the inhalation of the active agent in The patient's lungs. The unit dose may be, for example, from about 0.01 mg to about 1.5 g, depending on the dose of the active agent to be distributed. For example, the Unit dose can be from about 1 mg to about 100 mg or from about 10 mg to about 50 mg. Preferably, the unit dose is administered to the tongue, most preferably towards the front of the tongue behind the teeth, where it can be easily swallowed with or without the need for an additional fluid However, the invention contemplates the distribution to any part of the language, taking into account, for example, the taste sensations of the different sections of the language and / or preference of the individual patient associated with well-being, for example, the position of the mouth.

In certain embodiments of the invention, the average diameter of the drug particles is of a size that minimizes its ability to be inhaled in the lower lung. Typically, the average particle size of the agglomerate of the medicament particles is greater than 10 µm, preferably greater than about 50 µm or greater than about 75 \ mum. In certain embodiments of the invention, the range of Average particle size of the drug particles is from around 100 µm to about 1 mm. In the preferred embodiments, greater than 80% of the particles of medication have the diameter described above (no diameter medium), for example, 80% of the drug particles have a diameter greater than 10 µm, or a diameter from about 100 um up to about 1 mm. In other embodiments, greater than about 90% of the drug particles have the diameter previously described.

In certain embodiments of the invention, the average diameter of the drug particles does not vary in greater that about 20%, preferably not greater than about 15% and most preferably not greater than about 10%.

In certain embodiments of the invention, the multiparticles comprise a pharmaceutically excipient acceptable. The excipient preferably does not comprise more than around 20% of multiparticles by weight, preferably not more than about 10% by weight.

In certain embodiments of the invention, the excipient is coated with the medication, or the medication is coated with the excipient. Moreover, the medication and the excipient can be a mixture of powders, each being preferably greater than 10 µm, preferably greater than about 50 µm or greater than about 75 µm.

In certain embodiments of the invention, the excipient can provide taste masking medicine. In the taste masking embodiments and other embodiments, the excipient may include aromas and / or sweeteners In other embodiments, the excipient may provide a sustained or delayed release of medicine.

In certain embodiments of the invention, the Multiple doses of the medication are contained in a reservoir. He deposit can contain a number of multiparticles for provide any number of unit doses, for example, from about 2 doses up to about 400 doses. For ease in patient compliance, the deposit has an amount sufficient dose to provide, for example, a provision of days, a provision of months or a provision of years of doses, for example, 30 or 365 for a dosage once a day for a month or a year, respectively.

In certain embodiments, the system may contain multiple dosing mechanisms in order to provide different dosage amounts for different moments For example, the system can comprise two mechanisms dosage that can provide a dosage amount different in the morning and in the afternoon. In other embodiments, it You can adjust the dosing mechanism in order to increase or Decrease the dose size.

In certain embodiments, the system may contain more than one deposit, each containing a medicine or enantiomeric form of the different medication. Behind the drive, the desired amount of each medication is measured to distribution, such measure being present in the factory or other place, for example, a pharmacy. Such a system would be beneficial. for a combination therapy and would eliminate the need for multiple systems and would allow a much wider range of doses possible and dose combinations of what is possible to this.

In certain embodiments of the invention, the system distributes up to about 80%, preferably up to about 90% of the doses supplied in the system, eliminated thus waste providing an effective system.

In certain embodiments of the invention, the Variability between doses at doses is not greater than 5%.

In certain embodiments of the invention, the device comprises a nozzle. Preferably, the nozzle is of sufficient length to minimize exposure of the deposit to the humidity from the outside of the device. Preferably, the nozzle comprises a cap or nozzle closure to minimize moisture ingress (for example, from saliva or moisture) on the device In order to minimize the exposure of moisture deposit, the invention may also include a desiccant Additional measures can be taken by doing the device of a material that has water repellent properties to inhibit moisture accumulation. For example, the device it may consist of a material that does not get wet such as silicone which,  if it becomes contaminated with moisture, it would promote the formation of droplets that they would drain and not stick to the surface of the device and not they would result in water accumulation. In certain embodiments, the device (especially the nozzle) can comprise a plastic that contains silver or other resistant material to microbial growth.

In order to help the compliance of the patient, certain embodiments of the invention include a counter  or indicator to show the number of doses left in the system or number of doses operated.

In certain embodiments of the invention, the Unit doses are measured individually before actuation, by example, in the form of capsules or ampoules, in which each ampoule It contains a single unit dose. The system may be able to contain any multiple unit dose pre-measures, for example, from about 2 Up to about 400 blisters.

In certain embodiments of the invention, the system is able to be recharged with additional doses (in form deposit or pre-measures) after exhaustion complete or partial

On the other hand, the system can be manufactured in which the device is disposable and not capable of being recharged with additional unit doses.

The invention is related to distribution methods (eg, in vivo administration and ex vivo dispensing).

The present invention is also directed to systems containing particles greater than 10 µm of a particulate and particulate medicament of 10 µm or less of same or different medicine that, after actuation, distribute a unit dose for oral administration and pulmonary.

The present invention is also related with nozzles adapted to fit in a device distribution of medications to administer a medication in multi-particle form in a patient's oral cavity, being the improvement that the nozzle protrudes from the distribution device of medication at an angle in order to direct the multiparticles on the patient's tongue.

The present invention is also related with nozzles that are conical or rectangular in shape and that they provide a flared opening, in which the area of the nozzle outlet is larger than the area of the entrance of the nozzle. This reduces the speed of multiparticles distributed in order to minimize lung deposition.

The present invention is also related with nozzles that drop the unit dose vertically on the tongue with minimum or zero horizontal speed. This action directs the unit dose down to the tongue and minimizes movement of the particles towards the back of the throat in order to minimize or avoid lung deposition. In the realizations Preferred, when the device is used as intended, greater than 80% of the unit dose is administered from the device in a downward direction from around 45 degrees up to about 135 degrees, based on the baseline device independent vertical. Preferably greater than 90% of the medication follows this direction.

For the purposes of the present invention, the term "device" refers to an apparatus capable of Distribute a unit dose of medication.

The term "system" refers to a medication distribution device in combination with the multiparticle medicine described that has the specifications described in this specification, for example,  drug particle size, type of excipient, etc.

The expression "discrete collection" is refers to a freely flowing and uncompressed unit of multiparticles with minimal particulate matter that is dispersed in the surrounding environment (for example, as a cloud or fog).

The term "medication" refers to any agent that is capable of providing a therapeutic effect  to a patient after gastrointestinal deposition. This encompasses all medications that are intended for absorption for a systemic effect (regardless of its actual bioavailability) as well as medications intended for a local effect on the intestine and / or the oral cavity, for example, nystatin, antibiotics or local anesthetics.

The expression "particle size" is refers to the diameter of the particle.

The term "deposition" means the unit dose deposit at the intended point of absorption and / or action. For example, gastrointestinal deposition means the intended deposit of unit dose in the system gastrointestinal for, for example, absorption for an effect systemic or to exert a local effect. Lung deposition means the intended deposit of medication in the lungs with in order to provide a pharmaceutical effect, independently that the unit dose can enter the oral cavity before lung deposition

The term "dispense", when used in connection with the devices and systems of the present invention, means that the device or system distributes the unit dose ex vivo with the intention of subsequent administration to a mammal. For example, the device or system may dispense the unit dose into a food, a liquid, a spoon or other intermediate receptacle.

The term "administer", when used in connection with the devices and systems of the present invention, means that the device or system distributes the unit dose in vivo , that is, directly in the gastrointestinal tract of a mammal.

The term "distribute" is intended to cover all ex vivo and in vivo distribution, that is, to dispense and administer, respectively.

The term "patient" refers to beings humans as well as other mammals that need an agent therapeutic, for example, pets or livestock. This term also refers to humans or mammals that need or receive prophylactic treatment.

In certain embodiments, the particles are functionally defined with respect to the fact that they are of a size such that an effective dose cannot be distributed in the lung inferior of a human patient. However, this definition it should be understood that it means that a small percentage of medication (but not an effective amount to produce an effect therapeutic) can in fact be inadvertently distributed to patient's lungs Also, this definition is intended for define the particles, but not to limit the use of the invention to Human treatments only. The invention can be use to distribute doses of medications to other mammals too.

Brief description of the drawings

Fig. 1 is a schematic side view of a distribution device according to the invention in a position of foot; Y

Fig. 2 is a schematic side view of the device of Fig. 1 in the inverted position (distribution).

Fig. 3 is a vertical section through another form of distribution device according to the invention, which It has a mouthpiece;

Fig. 4 is a front view of the device of Fig. 3, with the nozzle folded in a position of storage;

Fig. 5 is a vertical section through a third form of distribution device according to the invention,  that has a mouthpiece;

Fig. 6 is a front view of the device of Fig. 5, with the nozzle folded in a storage position;  Y

Fig. 7 is a vertical section through a fourth form of distribution device according to the invention.

Fig. 8 is an illustration of an embodiment of the invention comprising a drum reservoir.

Fig. 9 is an illustration of an embodiment of the invention having a rotating part outside the Deposit.

Fig. 10 is an illustration of an embodiment of the invention having a rotating wheel outside the Deposit.

Fig. 11 is an illustration of an embodiment of the invention having a turntable mechanism.

Fig. 12 is an illustration of an embodiment of the invention having a sliding plate mechanism.

Fig. 13 is an illustration of an embodiment of the invention having an Archimedes screw.

Fig. 14 is an illustration of an embodiment of the invention having a sliding part mechanism.

Fig. 15 is an illustration of an embodiment of the invention having a sliding deposit mechanism.

Fig. 16 is an illustration of an embodiment of the invention having a pull cord mechanism.

Fig. 17 is an illustration of a container blister.

Fig. 18 is an illustration of a mechanism of opening for a blister strip or roll.

Fig. 19 is an illustration of a mechanism of perforation for a blister strip or roll.

Figs. 20 and 20A are illustrations of packaging circular blister

Fig. 21 is an illustration of a device of powder distribution comprising a lifting rod.

Fig. 22 is an illustration of a device powder distribution with a powder feeder optionally coupled.

Fig. 23 is an illustration of a device of dust distribution with an internal reservoir.

Fig. 24 is an illustration of a nozzle in angle.

Fig. 25 is an illustration of a nozzle curved

Fig. 26 is an illustration of a nozzle in right angle.

Fig. 27 is an illustration of a nozzle conical

Fig. 28 is an illustration of a nozzle rectangular.

Fig. 29 is an illustration of a nozzle rectangular resembling a fan.

Detailed description

In general, it has been recognized in the art that formulations for inhalation or insufflation of dry powder they can consist of particles of a size of about 2 micrometers in diameter so that the particles, when inhale, reach the peripheral or "deep" lung, including the alveoli. Particles larger than 10 micrometers in diameter they are not able to reach the deep lung when they are inhaled because they are collected in the back of the throat and in the upper airways in humans. Therefore, the known powder distribution systems have been formulated with particle sizes of less than 10 micrometers in order to the particles reach the intended site of action, the system pulmonary. Known dust distribution systems have not contemplated the distribution of particles from a device of multidose distribution to achieve gastrointestinal deposition and, therefore, have avoided the use of drug particles having a large size, for example, larger than 10 micrometers. Under the present invention, a surprising has been made discovery that drug particles greater than 10 micrometers can be distributed from a device distribution of multipurpose medication for deposition gastrointestinal in a patient in order to minimize the inhalation of the drug particles in the lungs, with the in order to have substantially all the dose deposited in the system gastrointestinal.

The present invention is directed to a system that it comprises a device that contains multiple doses of a medicine that is in the form of multiparticles. When it is activated the system, the device distributes a unit dose, preferably by administration in the oral cavity of a patient, so that the unit dose is deposited in the system Gastrointestinal tract for subsequent absorption and / or action. Preferably, the unit dose is subsequently swallowed by the patient for absorption and / or action in the stomach and / or bowels. However, the system can be used to distribute a unit dose of medication intended for absorption and / or action sublingual or oral.

In order to increase deposition gastrointestinal and reduce lung deposition, unit dose It is preferably administered in a discrete collection. The Unit dose administration as a discrete collection ensures that multiparticles are added together and there is no dispersion or "fog" that forms in the oral cavity that It would tend to be sucked into the lungs.

The average particle size of the medication the unit dose is greater than 10 µm and preferably greater than around 50 µm in order to minimize aspiration pulmonary medication so that an effective dose of said medicine cannot be distributed in the lower lung of a human patient For example, medication particles can be greater than about 75 µm, or greater than about 100 µm. A preferred range of average particle size of the medication is about 100 µm to about 500 um, although drug particles of 1 mm and above would be still functional in the present invention. Preferably any inactive particle in the unit dose is also higher than 10 µm in order to minimize pulmonary aspiration of such particles. In order to reach the desired size of medium particles, the active material can be incorporated into larger particles if the active agent itself is less than 10 \ mum. This can be accomplished by procedures known in the technique, for example, by granulation, coating, agglomeration or spray coating. The most particles large may include excipients suitable for use in pharmaceutical formulations

In the preferred embodiments of the invention, the average particle size of the multiparticle drug  does not vary by more than about 20%, more preferably no more than around 15% and most preferably in no more than about 10% Preferably, any inactive particle will also be within this interval.

In preferred embodiments, greater than about 80% of the drug particles enter within the variance described above, more preferably greater than 90% and most preferably about 100% of the particles of medication fall within the ranges described above. For example, in a preferred embodiment, about 90% of the unit dose medication particles would have a size of average particles from about 450 to about 550 µm, although this example does not mean that it is limiting. Preferably, any inactive particle also enters of this interval.

The unit dose size depends on the amount of medication needed to provide the effect intended therapeutic and the amount of any excipient pharmaceutically acceptable that may be necessary. Typically, a unit dose from about 0.01 mg to about 1.5 g it would be enough to contain a therapeutically effective amount of the medicine to be distributed, however, this interval It is not limiting and may be minor or major, depending on the amount of medication and excipient needed. Generally, the unit dose should not be so large that it is not able to be swallowed by the patient without much difficulty. Be prefer that the unit dose be of a sufficient amount small that can be swallowed without the need for a liquid additionally, however, the invention is not limited to such amount and doses that may require a liquid are contemplated by the invention. Preferably, the unit dose is from about 1 mg to about 100 mg, or from about 10 mg to around 50 mg, depending on the potency of the active agent. In situations where the unit dose is too large to be swallowed easily, it is contemplated that the system can be operated multiple times for subsequent distribution in order to administer divided doses of the intended dose, which are more easily swallowed by the patient.

When it is contemplated that the unit dose is swallowed without the use of an additional liquid, certain embodiments of the invention stipulate that the multiparticles comprise a effective amount of an agent that stimulates saliva production in order to facilitate the swallowing of the unit dose. Such agents include any acid that is safe for human consumption and include acids, acid anhydrides and food acid salts. Food acids include tartaric acid, malic acid, fumaric acid, adipic acid, succinic acids and fruit acids, For example, citric acid. The anhydrides of acid of the acids described above. Acid salts may include sodium salts, dihydrogen phosphate, disodium dihydrogen pyrophosphate, acid citrate and acid sulfite sodium

In other embodiments of the invention, the multiparticles may comprise a compound or composition effervescent that provides a pleasant organoleptic effect that can substantially mask the taste of active ingredients Unpleasant taste in the powder. Effervescent action too It acts as a stimulant for the production of saliva. The agents Effervescent include compounds that give off gas. The agents Preferred effervescent release gas through reactions chemicals that occur after exposure to a liquid such as saliva in the mouth This chemical reaction that generates bubbles or gas it is most frequently the result of the reaction of an acid (for example, saliva stimulating acids listed above) and an alkali metal carbonate / dicarbonate or base. The reaction of these two general classes of compounds produces Carbon dioxide gas after contact with saliva.

The use of effervescent acids and / or ingredients It is particularly useful in patients with achlorhydria.

For ease of swallowing and in order to minimize pulmonary aspiration of multiparticles, the system will preferably set to dispense the unit dose on the Patient's tongue The tongue can be taken out in order to facilitate the deposit of the unit dose on it or, preferably, the dispensing can be configured in order of depositing the unit dose on the tongue without the need for the Patient stick out your tongue. Preferably, the system is one configuration such that the unit dose is deposited behind the teeth towards the front of the tongue. The front of the tongue in order to stimulate the natural swallowing of the dose unit in the esophagus. This reduces the possibility that any individual particle is carried by air and inhaled in the pulmonary system and facilitates swallowing the unit dose by starting a more natural swallow reflex. However, the unit dose should be able to be placed anywhere on the tongue, including the deposit on the back of the tongue without stimulate the palate veil to produce a reflection of obstruction.

As with most formulations pharmaceutical, it is often necessary to add an excipient Pharmaceutically acceptable to the medicine. For example, when formulates an agent in tablets or capsules, an agent of dough in order to provide enough dough to compress or encapsulate the agent. This results in many of the drawbacks of the solid dosage forms that were discussed above.

With the present invention, however, it is not it is necessary to have a large percentage of the formulation that consists in the excipient, since it is preferable to have the unit dose that be deposited on the patient's tongue as small as possible in order to facilitate swallowing. The use of excipient is used in the present invention, for example, to improve fluidity, to mask the taste, to stimulate the flow of saliva to swallow or to provide a modified release of medicine. In preferred embodiments, the excipient is less than about 20% by weight of multiparticles and more preferably less than about 10% by weight of the multiparticles These weight percentages of preferred excipients They do not mean that they are limiting. For example, with a medication of microdoses, such as digoxin or levothyroxine, the percentage of excipient may need to be greater than 20% in order to provide sufficient mass for an acceptable flow or dose measurement characteristics.

The pharmaceutically acceptable excipient of Multiparticles can coat the medication. In such an embodiment, the excipient can provide a modified release of the medicine. For example, such multiparticulate material can be formulate to provide a delayed release in which the Medication is released in the intestine. It can also be formulated multiparticulate material with an excipient coating in order to provide a sustained release of the medication over time in the gastrointestinal tract. Can also be done coat the medication with excipient in order to mask a Bitter taste of certain medications.

On the other hand, the excipient can be used as a substrate and the medicament can be coated on the excipient. This formulation option can be used in order to provide the desired flow capacities and to provide a mass critique of drug particles in order to minimize the lung aspiration.

The excipient can also be used in a mix with the medicine in order to provide the properties  desired (for example, flow properties) to allow the Unit dose is distributed as a discrete unit with minimum multiparticles suspended in the air.

When multiparticles are formulated as controlled release powders, the drug can be combined with a polymer that can be soluble, insoluble, permeable, waterproof or biodegradable. The polymers can be polymers or copolymers The polymer can be a natural or synthetic polymer. Natural polymers include polypeptides, polysaccharides and alginic acid An appropriate polypeptide is zein, and a Appropriate polysaccharide is cellulose. Combining medicament / polymer can be formed by known methods such as granulation, spray coating or agglomeration.

Representative synthetic polymers include alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitrocelluloses, acrylic acid polymers and methacrylic and its esters, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, poly (alkylene oxides), poly (alkylene terephthalates), poly (alcohols vinyl), poly (vinyl ethers), poly (vinyl esters), poly (vinyl halides), polyvinylpyrrolidone, polyglycolides, polysiloxanes and polyurethanes, and their copolymers. He polymer to be used is determined by its toxicity and its compatibility with the particular active ingredient to be used and can be selected without difficulty by experts in the technique.

Particularly suitable polymers include: methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, acetate cellulose, cellulose propionate (lower molecular weight, medium or higher), cellulose acetate propionate, acetate butyrate cellulose, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, sodium salt of cellulose sulfate, poly (methyl methacrylate), poly (methacrylate ethyl), poly (butyl methacrylate), poly (methacrylate) of isobutyl), poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (methacrylate lauryl), poly (phenyl methacrylate), poly (acrylate) methyl), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (acrylate octadecyl), polyethylene, low density polyethylene, polyethylene High density, polypropylene, polyethylene glycol, poly (oxide of ethylene), poly (ethylene terephthalate), poly (alcohol vinyl), poly (vinyl isobutyl ether), poly (vinyl acetate), poly (vinyl chloride) and polyvinylpyrrolidone. The especially suitable copolymers include: butyl methacrylate / methacrylate copolymer isobutyl, methyl vinyl ether / acid copolymer high molecular weight maleic, copolymer of methyl vinyl ether / monoethyl acid ester maleic, methyl vinyl ether / anhydride copolymer maleic and vinyl alcohol / vinyl acetate copolymer.

Representative biodegradable polymers include polylactides, polyglycolides, poly (terephthalate ethylene), polyhydroxybutyrate, polyhydroxivalerate and polyurethane.

Acrylates and representative methacrylates are polyacrylic and polymethacrylic polymers such as those sold under the trademarks Eudragit, Amberlite and Carbopol.

Classes of medications that are appropriate in the Present invention include antacids, substances anti-inflammatory, coronary dilators, cerebral dilators, peripheral vasodilators, anti-infective, psychotropic, antimaniacs, stimulants, antihistamines, laxatives, decongestants, vitamins, gastrointestinal sedatives, antidiarrheal preparations, antianginal drugs, vasodilators, antiarrhythmics, antihypertensive medications, vasoconstrictors and migraine treatments, medications anticoagulants and antithrombotic, analgesic, antipyretic, hypnotics, sedatives, antiemetics, anti-nausea, anticonvulsants, neuromuscular medications, hyper-e agents hypoglycemic, thyroid and antithyroid preparations, diuretics, antispasmodics, uterine relaxants, mineral additives and Nutritional, anti-obesity medications, anabolic medications, erythropoietic, anti-asthmatic, bronchodilator medications, expectorants, cough suppressants, mucolytics, medications that affect calcification and bone production and medications anti-headphones

Specific medications include sedatives gastrointestinal, such as metoclopramide and bromide propanteline; antacids such as aluminum trisilicate, aluminum hydroxide, ranitidine and cimetidine; medicines anti-inflammatories such as phenylbutazone, indomethacin, naproxen, ibuprofen, flurbiprofen, diclofenac, dexamethasone, prednisone and prednisolone; coronary vasodilator medications such as glyceryl trinitrate, isosorbide dinitrate and tetranitrate pentaerythritol; peripheral and cerebral vasodilators, such such as soloctidilum, vincamine, naphthrofrofil oxalate, mesylate co-dergocrine, cycladelate, papaverine and acid nicotinic; anti-infective substances such as stearate erythromycin, cephalexin, nalidixic acid, hydrochloride tetracycline, ampicillin, flucloxacillin sodium, mandelate hexamine and hexamine hippurate; neuroleptic medications such such as flurazepam, diazepam, temazepam, amitriptyline, doxepine, lithium carbonate, lithium sulfate, chlorpromazine, thioridazine, trifluperazine, fluphenazine, piperothiazine, haloperidol, maprotiline hydrochloride, imipramine and demethylimipramine; central nerve stimulants such as methylphenidate, ephedrine, epinephrine, isoproterenol, amphetamine sulfate e amphetamine hydrochloride; antihistamine medications such such as diphenhydramine, diphenyl spiraline, chlorpheniramine and brompheniramine; antidiarrheal medications such as bisacodyl e magnesium hydroxide; the sulphosuccinate laxative drug from dioctyl and sodium; nutritional supplements such as acid ascorbic, alpha-tocopherol, thiamine and pyridoxine; antispasmodic medications such as dicyclomine and diphenoxylate; medications that affect the rhythm of the heart such such as verapamil, nifedipine, diltiazem, procainamide, disopyramide, bretilium tosylate, quinidine sulfate and gluconate quinidine; medicines used in the treatment of hypertension such as propranolol hydrochloride, guanetidine monosulfate, methyldopa, oxprenolol hydrochloride, captopril and hydralazine; medicines used in the treatment of migraine such as ergotamine; medicines that affect the coagulability of the blood such as epsilon-aminocaproic acid and protamine sulfate; analgesic medications such as acid acetylsalicylic, acetaminophen, codeine phosphate, sulfate codeine, oxycodone, dihydrocodeine tartrate, oxycodeinone, morphine, heroin, nalbuphine, butorphanol tartrate, hydrochloride pentazocine, cyclazacin, pethidine, buprenorphine, scopolamine and mefenamic acid; antiepileptic medications such as phenytoin sodium and sodium valproate; neuromuscular medications such as dantrolene sodium; substances used in the treatment of diabetes such as tolbutamide, disbenase glucagon and insulin; medicines used in the treatment of dysfunction of the thyroid gland such as triiodothyronine, thyroxine and propylthiouracil; diuretic medications such as furosemide, chlorthalidone, hydrochlortiazide, spironolactone and triamterene; he uterine relaxant drug ritodrine; appetite suppressants such as fenfluramine hydrochloride, phentermine and hydrochloride diethylproprion; anti-asthmatic and bronchodilator medications such as aminophylline, theophylline, salbutamol, sulfate orciprenaline and terbutaline sulfate; expectorant medications such as guaifenesin; cough suppressants such as dextromethorphan and noscapine; mucolytic medications such as carbocysteine; antiseptics such as cetylpyridinium chloride, thyrotricin and chlorhexidine; decongestant medications such as phenylpropanolamine and pseudoephedrine; hypnotic medications such as dicloralfenazone and nitrazepam; anti-nausea medications such as promethazine theoclate; hemopoietic medications such as ferrous sulfate, folic acid and calcium gluconate; medicines uricosuric agents such as sulfinpyrazone, allopurinol and probenecid; Y agents that affect calcification such as bisphosphonates, by example, etidronate, pamidronate, alendronate, residronate, Teludronate, Clodronate and Alondronate.

Medicines that have taste and / or smell characteristics that, when administered orally without any excipient, make the drug or therapeutic agent unpleasant on the palate for a subject and would be candidates for masking of the flavor in the present invention include, but are not limited to, H2 receptor antagonists, antibiotics, analgesics, cardiovascular agents, peptides or proteins, hormones, agents antimigraña, anticoagulant agents, antiemetic agents, agents antihypertensives, narcotic antagonists, chelating agents, antianginal agents, chemotherapy agents, sedatives, antineoplastic agents, prostaglandins, diuretic agents and Similar. Typical medications include, but are not limited to, nizatidine, cimetidine, ranitidine, famotidine, roxatidine, ethinidine, lupitidine, nifentidine, niperitone, sulfotidine, tuvatidine, zaltidine, erythromycin, penicillin, ampicillin, roxithromycin, clarithromycin, psylium, ciprofloxacin, theophylline, nifedipine, prednisone, prednisolone, ketoprofen, acetaminophen, ibuprofen, dexibuprofen lisinate, flurbiprofen, naproxen, codeine, morphine, diclofenac sodium, acetylsalicylic acid, caffeine, pseudoephedrine, phenylpropanolamine, diphenylhydramine, chlorpheniramine, dextromethorphan, berberine, loperamide, acid mefenamic, flufenamic acid, astemizole, terfenadine, certirizine, phenytoin, guaphenesin, N-acetylprocainamide HCl, its pharmaceutically acceptable salts and derivatives.

Dry powder inhalation devices require high air flow to create conditions of sufficient shear to isolate the drug particles separated in the pulmonary system. The higher the flow of air, the more the device disperses the medicine the powder in Smaller and more breathable particles. This air flow is in the range of about 20 liters / min to about 150 liters / min and results in high shear forces on the agglomerates of medicine and produces collisions between powder drug agglomerates both of which tend to deagglomerate large agglomerates into primary particles desired for lung deposition. In certain embodiments of the present invention, the air flow provided is sufficient to facilitate the unit dose of medication to leave the device, but not enough in order to project the particles in a "fog" for inhalation in the system pulmonary. This air flow is less than 20 liters / min, preferably less than about 10 liters / min. In the In the present invention, prior art devices are can modify in order to provide air flow desired less than 20 liters / min. In alternate embodiments, there are minimum air flow and dust is dispensed from the device in the oral cavity by gravitational force or mechanism of action. In certain embodiments, the unit dose is measured and moves mechanically to the dispensing hole of the device (against or in the direction of gravity) before dispensing.

In certain embodiments, multiparticles They are contained in a warehouse. Preferably, the deposit Contains multiple doses of multiparticles in order to provide a multiplicity of unit dose. The number of doses unit contained in the warehouse and capable of being distributed by the system depends on, among other factors, the frequency of the dosage and duration of therapy of the medication that is going to dispense For example, for acute therapy, the system may be configured to distribute 30 unit doses of an antibiotic that be prescribed three times a day for 10 days. On the other hand, For chronic therapy, the system can be configured to contain 30, 100 or even 365 doses of a medicine antihypertensive administered once a day.

In certain embodiments, the system of the invention in which the tank is replaceable, by example, in the form of a replaceable cartridge, or in which the deposit is able to be refilled, for example, including a removable cap, in which the bulk powder can be Introduce. However, in the embodiments in which the system is capable of being filled, it is preferable that the system uses a replaceable system such as the cartridge device previously described rather than filling the system with bulk powder to through a hole without a plug since the latter can be more prone to human error, for example, dust loss due to splash or improper handling. In addition, powder handling in bulk may result in contamination of the deposit, dust or both with moisture and / or contaminants.

In other embodiments, the system may be disposable, in which, after administration of all unit dose, the system is not able to be replaced with doses additional unit of medication. This embodiment can be beneficial for many reasons. Most prominently, a system disposable will give the patient, the prescriber and the manufacturer greater guarantees that the patient is receiving a dosage appropriate from a functional system that has not been subjected to inappropriate handling and / or internal friction for a long time duration of time Such a disposable device can also reduce the overall manufacturing cost, since the device only It would have to be manufactured to provide an exact dose for a finite period of time. With refillable systems, greater care should be taken in the manufacturing process and the materials be selected in order to ensure that the device is able to provide an exact dose during a longer period of time, for example, for a year. How compromise between the disposable and refillable system, you can manufacture a refillable system in which the patient is informed that after a certain amount of time and / or treatments of therapy, the system would be replaced by a new device. Such system would be beneficial for the patient, the prescriber and the manufacturer reducing manufacturing cost, improving patient comfort by being able to refill the device and assure all parties that a patient will not be using a device that may be non-functional due to internal friction and / or inappropriate handling.

In certain embodiments, it can be included in the system a counter that can improve patient comfort. This is done so that the meter or indicator is used to know how many doses have been taken by those patients who Sometimes they forget if they have taken a previous dose. With ways of solid dosage, if a patient has forgotten if it has been taken a previous dose, it is often necessary to count the remaining doses to see if one was taken. This creates problems such as pollution and also the probability of miscalculating so the patient can take a double dose or skip a dose due to a counting error. The counter will also keep the user informed when the medication will end and help improve proper planning for frequent patient a pharmacy timely. This can reduce the likelihood of a patient be "surprised" when the system no longer provides unit dose. The device can count, on the other hand, the distributed doses counting forward, or you can count towards back to show the number of doses left in the system. He counter can be an electrical or mechanical mechanism that are commonly known in the art. The indicator can also be a visual mechanism, for example, dust could fall below of a colored marker that would indicate the number of doses that left, the device can expose the internal dust in sight in a window or other mechanisms known in the art.

In the present invention, unlike the tablets or capsules that have instruction labels for the patient on the secondary vessels, the system of the The present invention has a label permanently attached to the container by the manufacturer, presciptor or dispensing. As the medication is not separated from the container, the label is not dissociated from the medication and the label can be seen in or between each dose

In certain embodiments, the unit dose of multiparticles are measured outside the tank and expelled from the device. Preferably, the unit dose leaves the tank at a distribution duct that carries the unit dose outside the device to the patient's oral cavity or a receptacle intermediate. The distribution conduit can be a hollow tube or a molded duct with a hollow center where you can transport unit dose. In certain embodiments, the dose unit passes through the distribution conduit to the oral cavity due to the severity in which it is necessary to keep the unit in vertical position during drive and distribution. Do not However, it is contemplated in certain embodiments of the invention that distribution outside the tank and through the conduit to Unit dose distribution can be facilitated by the use of an aqueous gas or vehicle. For example, a gas can be released after the drive to facilitate movement out of the device unit dose. The gas may be pressurized and placed in an additional deposit in the system or it may be compressed in the same tank as multiparticles. The gas pressurized can be compressed air or liquid gas that becomes in gas after the container is released. In another embodiment, it you can release a liquid from a separate tank in which the multiparticles and the liquid are mixed after actuation and a liquid suspension of the multiparticles is deposited in the oral cavity of the patient.

In preferred embodiments, the system administer the unit dose against gravity by mechanical means. In such an embodiment, the reservoir or vial containing the dose unit are at a point below the mouth before the administration and, after actuation, the unit dose moves against gravity to the outlet cavity, where it is deposited on language. At the point of deposit gravity can be used. This provides a more comfortable and appropriate movement for the patient, rather than the alternative where the unit dose is in a point higher than the oral cavity and is transported with, or help by, gravity to the point of departure. For example, a sipping straw has a more comfortable and appropriate touch for a user when the content is sucked up to the tongue rather than lowered from the point of origin, for example, the deposit.

It is also contemplated that the unit dose may be mechanically expelled from the device, for example, by the action of a piston, worm or similar mechanism. This can be used in order to ensure that the entire unit dose is expelled from the device. For example, if there is contamination of moisture at the point of expulsion, an amount of the unit dose It can stick to the device. A plunger, worm or similar mechanism would minimize or eliminate this possible situation.

As previously described, it is contemplated that the unit dose may, in some circumstances, be expelled not inside the oral cavity, but in a drink, food, support (for example, a spoon) or other appropriate intermediate receptacle before ingestion

Detailed description of certain embodiments

With reference to Fig. 1, a device of distribution (1) has a housing (2), which includes a base (3) and an exit portion (4). Inside the case there is a camera (5) of circular cross section. The camera contains a load (6) of a pharmaceutical particle preparation, for example, a powder or granular preparation, comprising a medicament orally active In the upper extremity of the chamber (5) there is a distribution duct (7) that communicates with an outlet of distribution (8). A cover (9) can cover the outlet (8) and can be joined by means of friction adjustment or snap adjustment (not shown in the drawings) to the circumferential surface of the housing (2). A measuring device (10) is provided in the chamber periphery (5) for the purpose of measuring a dose of the preparation from the chamber (5) and download the dose measured in the distribution duct (7). The measuring device, which is not shown in Fig. 1, can be, for example, of a class used to measure dry powder formulations in dry powder inhalers. An appropriate form of such a measuring device is described in The specification of European Patent No. 0 661 071B.

Fig. 2 shows the device of Fig. 1 in inverted position. As a result of the investment, the preparation it is placed immediately adjacent to the distribution duct (7) and the measuring device (10). When operating the measuring device (in the case of devices such as those of EP 0 661 071B, per rotation), a dose of the preparation is measured and discharge into the distribution duct (7), through which it falls under the influence of gravity at the distribution outlet (8). If desired, the dispersed dose can be collected in a receptacle (eleven).

The use of rotating measuring devices such as those known in the art of powder inhalers Dry is often necessary for the user to use both of your hands to use the device as a result of the action of torque required to operate the measuring device. It is conceived that the device of the invention can be provided with a means of gear that communicates between the rotating device and a remote drive device on the housing of the device, the drive device being arranged remote to allow the drive using the hand on which it Hold the device. The remote drive means can be, for example, operable by pressing or squeezing or a tab or button.

With reference to Fig. 3, in another form of device according to the invention the medicine can be distributed directly in the patient's mouth. The device of Figs. 3 and 4 has an elongated housing (21), in which a Shallow drum-shaped tank (22) containing the particulate material (23) to be dispensed. The axis of tank (22) extends transversely across the elongated housing and the reservoir (22) has a diameter that is greater than the width of the housing (21), so that the tips of the tank are extend outside the sides of the housing. The deposit (22) is swivel and can be arranged to measure the material in particles (23) analogously to that described above in relationship with Figs. 1 and 2. A distribution conduit is provided (24) in the housing below the tank (22) to receive the measured doses of material from it to distribute to an opening (25). A nozzle (26) is positioned against the housing around the opening (25).

A passage (27) defined inside the nozzle (26) communicates with the opening (25) to receive the material in particles from there. In the housing (21) an opening is provided to the air with a valve (neither shown) and also communicates with the distribution duct (24) so that the air can be sucked through that air opening when a patient sips through the mouthpiece. The valve is arranged way that allows only a limited amount of air, in general less than 20 cm3, be aspirated through the opening during a single patient sipping action, closing the valve after the amount of air has passed to prevent Let more air be sucked.

The nozzle (26) has an elongated part (28) immediately adjacent to the opening (25). Extending from the elongated part (28) at the distal end relative to the housing (21) there is a flared part (29) that defines an output of distribution (30) that looks down. Below the part elongated (28) a stop piece (31) is provided that serves to indicate to the user the correct insertion depth in the mouth of the nozzle (26). The nozzle (26) is mounted on a pivot (32), around which the nozzle is pivotable from the position working to a storage position. The position of storage is indicated in Fig. 3 by dashed lines. When the nozzle (26) is in storage position, the opening (25) at the outlet of the distribution duct (24) is it can be closed by means of a sliding closure plate (33), which protects against moisture entering the tank (22) between Dispensing operations By releasing the nozzle (26) from the storage position, drive means (no shown) are operable to operate the mechanism of dispensing (including deposit 22) and a dose counter. In Fig. 4, the device with the nozzle (26) is shown in storage position

The configuration and relative dimensions of the nozzle (26) of the device of Figs. 3 and 4 are chosen to ensure that substantially all particulate material dispersed (23) is distributed to, and deposited in, the mouth of the patient. In particular, they are chosen in order to prevent accidental inhalation of the material. Therefore, the elongated part (28) of the nozzle (26) defines a fluid channel (27a) of section relatively small cross section (for example, section 5 mm diameter circular transverse) which, at the end distal, camped out at a distribution outlet (30) in which the passage (27b) is of cross section much more big. In addition, the distribution outlet (30) is oriented towards down. Flare of the distal part of the passage (27b) tends to produce deceleration of the material carried by the received air from the channel (27a), and that deceleration, in combination with the exit orientation (30), encourages material deposit inside the patient's mouth and especially on the tongue. In addition, as discussed further below, the material in particles will thus be preferably formulated to minimize the amount of material that will remain airborne in the administration and, therefore, minimize inhalation.

The device (34) of Figs. 5 and 6 is similar to that of Figs. 3 and 4, and the parts present in Figs. 3 and 4 are designated by the same reference numerals in the Figs. 5 and 6. In addition to the structures already described in relation to Figs. 3 and 4, the device of Fig. 5 contains a reservoir additional (35) with associated measuring medium (not shown) and associated distribution duct (36). The ducts of distribution (24) and (36) communicate with the passage (27) in the nozzle (26) for the distribution of the particulate material a them from the respective deposits (22) and (35). In Fig. 6, the device of Fig. 5 is shown with the nozzle (26) in storage position Deposit (35) will normally contain a particulate material (37) comprising a medicament orally active that is different from the orally active medication in the particulate material (23), although it will be appreciated that, if you want, the material (37) could contain the same medicine orally active, for use as a reserve source or for use in A different dosage. For example, one of the deposits can contain one medication of glitazone, while the other may then contain a sulfonylurea. The choice of others routine combinations for those skilled in the art, taking into account the known activities of medications and Any relevant contraindication.

The device (38) of Fig. 7 is, in some aspects, similar to the device (20) of Figs. 3 and 4 and the pieces present in Figs. 3 and 4 are designated by them reference numerals in Fig. 7. In the case of the device (38), however, a deposit (39) is additionally present and measuring means (not shown) for a second material in particles (40) comprising an inhalation medicament. He device has a distribution conduit (41) into which it enters in use the material measured from the tank (39). Duct of distribution communicates with an inhalation airway (42), which is ready to receive material from the duct (41). The path from the reservoir (22) via the conduit of distribution (24) to the nozzle (26) and the path from the reservoir (39) via the distribution duct (41) to the airway (42) are independent of each other. While, as described in relationship with the device (20) in Figs. 3 and 4, the conduit of distribution (24) communicates with an air opening that has a valve that limits the entry of air, the distribution duct (41) communicates with a separate air opening in the housing that allows the admission of essentially unrestricted air into the patient inhalation via the airway (42). The device includes selection means (not shown) that are operable by the patient to select which of the materials (23) or (40) is going to manage. According to the selection made by the patient, the air path that communicates with the distribution duct of the material not selected.

In contrast to the flared exit (30) of the nozzle (26), the airway (42) of the device (38) is sectional substantially constant or even tapered transverse and is tilted only slightly down. As a result, the flow of Airway air (42) tends to flow at a speed relatively high, and possibly even to be accelerated. This, in combination with the orientation of the exit of the airway, tends to encourage inhalation of particulate material. Appropriate combinations of particulate materials for use in deposits (22) and (39) include those comprising any of the orally active medications already mentioned above (in the case of deposit 22) and those comprising any medication that is appropriate for administration by inhalation (in the case of deposit 39), provided, of course, the medications selected are compatible use. Appropriate medications for inhalation will include, but are not limited to, those for use in the treatment or prevention of respiratory disease.

The device of Fig. 7 is especially appropriate for administration where there is a need for both Quick response as for continued action. For example, in the case of pain control, there is often a need for a rapid pain relief when starting treatment, being maintained After pain relief. Another potential area of use is the treatment of respiratory disease by means of a medicine inhalable during the day and through a medication orally active that acts more slowly for use at night.

In certain embodiments, as shown in the Fig. 8, the system comprises a device comprising a drum (81) which has an inner cavity (82) arranged therein to contain the multiparticles (83). The drum that has a outer covering (84), a rotating inner covering (85) disposed immediately inside the outer covering and a stationary retention band (86) located immediately inside a part of the inner lining. The coating exterior has a dispensing hole (87) at one point per below the retention band to dispense the unit dose and the Swivel inner lining has a filling hole (88) arranged in it. The rotating inner lining has a first portion (89) where the filling hole is not adjacent to the retention band to allow a dose to be filled in it multi-particle unit; and a second position (810) where said filling hole is adjacent to the retention band and in communication with the outer hole. After actuation, the inner lining moves from the first position to the second position and the unit dose is distributed from the tank to the dispensing hole and expelled from the device for distribution to the patient In this embodiment, the drum that Contains multiparticles can be spherical or cylindrical.

In another embodiment, as shown in Fig. 9, the system comprises a device comprising a reservoir (90) which contains the multiparticles (91), which has an orifice of exit in it (92); a rotating part (93) outside the tank that it has an external cavity (94) in communication with the orifice of output when the rotating part is in a first position, to allow a unit dose of the multiparticles; a stationary retention housing (95) that covers the rotating part very tightly, having the housing of retain a dispensing hole (96) disposed therein; the rotating part having a second position in which the external cavity of the rotating part is in communication with the dispensing hole in which, after actuation, the part swivel moves from the first position to the second position whereby the unit dose is distributed from the tank to the dispensing hole and expelled from the device to distribution to the patient

In another embodiment, as shown in Fig. 10, the system comprises a device comprising a reservoir (101) containing the multiparticles (102), having the deposit an exit hole in it (103); a rotating part (104) outside of the deposit having a plurality of external cavities (105); a stationary retention housing (106) that covers very tightly the rotating part, having the retention housing a dispensing hole (107) disposed therein; being the rotating part in position where an external cavity is in communication with the exit hole, to be filled with a unit dose of multiparticles, and an external cavity is in communication with the dispensing hole; being rotatable the rotating part to advance each cavity to the exact position of the next adjacent cavity in which a unit dose of the multiparticles is distributed from the dispensing hole when a cavity containing a unit dose is advanced to be in communication with the dispensing hole.

In another embodiment, as shown in Fig. 11, the system comprises a device comprising a reservoir (111) to contain the multiparticles (112), having the deposit an outlet (113) in it; a movable plate (114) that has a filling hole (115) disposed therein, having the plate mobile a first position in which the filling hole is in communication with the outlet opening of the tank; a plate of stationary retention (116) immediately below the movable plate to form a filling cavity with the filling hole, to be filled with the multiparticle unit dose when plaque mobile is in the first position, having the retention plate stationary a dispensing hole (117); having the plate movable a second position in which the filling hole is in communication with the dispensing hole. Behind the drive, the movable plate moves from the first position to the second position and a unit dose is distributed from the deposit to the dispensing hole, where it is expelled from the device and administered to the patient. In one embodiment Alternatively, the device has a stationary top plate (118) immediately on the movable plate, having the plate upper one hole in it in communication with the hole of the reservoir and filling hole in order to retain the dose unit in the cavity during transmission from the first to The second hole. In certain embodiments, as shown in Fig. 11, the mobile plate (114) is circular and moves so rotating from the first position to the second position. In others embodiments, as shown in Fig. 12, the movable plate (114) It is rectangular and moves slider from the first position to the second position.

In another embodiment of the invention, the system comprises a device comprising an Archimedes screw (131) capable of reciprocating motion to dispense a unit dose of multiparticles from the tank (132) to be discharged from the device to the patient's oral cavity.

In another embodiment of the invention, as shown in Fig. 14, the system comprises a device that it comprises a gap (141) in communication with a tank (142) and a distribution duct (143) in communication with the hole, in the that said device is capable of providing a unit dose of medication from the reservoir to the distribution duct. In certain embodiments, the device further comprises a piece Sliding (144) inside the tank and the hole, having the piece a filling cavity (145) slidable disposed therein, having the sliding part a first position with the filling cavity located in the tank and a second position with the cavity of filling located in the hole and in communication with the outlet of distribution. After the drive, the sliding part moves from the first position to the second position and a unit dose of the medication is discharged from the reservoir into the conduit of distribution and later in the oral cavity of the patient. In preferred embodiments, a mechanism, for example, a spring, (146), returns the sliding piece to the first position after the loose unit dose. In an alternative embodiment, such as is shown in fig. 15, the sliding piece is the tank (147) which is closed inside a housing (148).

In another embodiment of the invention, as shown in Fig. 16, the system comprises a device that it comprises an elongated tube (161) having an inner cord (162), the inner cord having a plurality of nodules (163) evenly spaced that close the tube to form a plurality of airbags (164) evenly spaced within of the tube, each of which contains a unit dose of multiparticles (165); in which, after actuation, it is pulled of the cord to expose a single air bag and unit dose it is dispensed from the system and subsequently dispensed to the oral cavity of the patient.

In certain embodiments of the invention, the Unit doses are measured individually before actuation. The Fig. 17 illustrates an embodiment comprising unit dose contained in ampoules (171) on a substrate base (172), each ampoule containing a unit dose, the basis of substrate and blisters covered by a closure (173). In certain embodiments, the blisters are linearly aligned in the form of a strip and, in alternative embodiments, the strip is in the form of a roll.

In certain embodiments of the system that it comprises previously measured ampoules, as shown in Fig. 18, after actuation, the strip or blister roll is advanced by means of a gear mechanism (180), a closing amount covering a blister is taken by a first roller roller (181) and an equal portion of substrate base is taken by a second winding roller (182), whereby a multiparticle unit dose from the strip and dispensed from the system to the oral cavity of the patient. Preferably, it use tension rollers (183) in order to smooth the base of substrate to facilitate the winding and storage of blister substrate used.

In other embodiments of the system comprising pre-measured ampoules, as shown by Fig. 19, the system further comprises a sharp piece (191), in which the strip is advanced until a blister is aligned with the sharp piece in which, after actuation, the sharp piece penetrates the blister and a multiparticle unit dose is expelled from the strip and dispensed from the system within the oral cavity of the patient.

In embodiments of the system comprising pre-measured ampoules, the substrate base is a disc shaped with the blisters arranged on the periphery of the disk. The blisters are equidistant from each other and from the center of the container, as shown in Fig. 20, in which, after drive, the substrate base revolves around its central axis and place a blister in alignment with a sharp piece. The sharp piece penetrates the blister and a unit dose from the blister to be dispensed from the system inside the cavity Oral of the patient. In alternative embodiments, the blisters are they can order as a matrix, as shown in Fig. 20a, which it would require a more complex mechanism in order to advance the blisters to the sharp piece, or vice versa.

Another embodiment of the invention, as shown in Fig. 21, is directed to a device for depositing a multiparticulate unit dose comprising a medicament in the tongue of a patient, which comprises a housing (211) that has an inner cavity (212) formed therein to contain multiple multiparticle dose (213), the housing having one end tapered upper (214) with an opening in it (215) and one end tapered bottom (216); a lifting rod (217) adjusted to a first position (218) inside the tapered lower end of the housing that is movable to a second position (219) within the tapered upper end of the housing, comprising the rod lifting an elongated cylinder (220) with an upper end (221) and an inner push rod (222) inside the elongated cylinder ending at a point below the upper end of the cylinder  to form a filling cavity (223) when the rod lift is in the first position (b), the pushrod inside is movable to end at a point above the end top of the cylinder when the lift rod is in the second position (d); in which, when the device is in vertical position in the first position, the cavity of filled with a unit dose of multiparticles and when the lifting rod moves to the second position, the rod of inner thrust moves to a point above the end upper cylinder and medication unit dose is expelled from the housing on the patient's tongue (f). This realization of the invention may further comprise a terminal cover (224) that cover the tapered upper end opening or at least one shutter (225) covering the tapered upper end opening, in which at least one shutter opens when the lift rod It is in the second position. This embodiment of the invention can further comprise an inner groove (226) in the opening of the tapered upper end, the inner groove being configured to fit and stop the movement of the elongated cylinder and not the inner push rod, allowing the push rod inside end at a point above the upper end of the cylinder to expel unit dose. Rod placement of internal thrust in the elongated cylinder in the first position is preferably adjustable in order to vary the volume of the filling cavity and individualize the dose of the medication. Preferably, the tapered upper end is of length enough to allow the dose to be deposited on the back of The patient's tongue In certain embodiments, the device will can load with the medicine and be lifted to a position between the first and second position before the drive, as It is shown in (c).

Another embodiment of the invention, as shown in Fig. 22, is directed to a device for depositing a medicine on a patient's tongue, which comprises a elongated housing (221) having an inner cavity (223), the housing having an opening (224) that connects the cavity inside the housing outlet, the housing being adapted to fit into the oral cavity of a human patient with the opening facing the patient's tongue; a moving part (225) inside the inner cavity, the moving part having a filling opening (226) capable of containing a dose of medication, the filling opening being closed by the housing when the moving part is in a first position (e), the moving part capable of being positioned in a second position (f) in which the filling opening is in communication with the opening of the housing to load the medicine into the opening or to Download the medication on the patient's tongue. In certain embodiments, the moving part is horizontally slidable from the first apposition to the second position or is rotatable within the elongated housing and rotates from the first position to the second position (h, i). Preferably, the elongated housing is of long enough to allow the medicine to deposit on the back of the patient's tongue. This realization also may comprise a powder feeder (227) coupled to the housing opening to deposit a unit dose of medicine in the opening when the moving part is in the second position, the powder feeder being completely removable the housing in order to allow the deposit of the dose on the Patient's tongue In preferred embodiments, the Powder feeder is attached to the housing by a folding piece (for example, a hinge, a spring, a flexible strip or mechanism similar) that provides a closed position and a position open When the housing and the powder feeder are in closed position, the powder feeder is coupled to the opening of the housing and is in position to deposit a dose medication unit in the filling opening (226) with the part mobile in second position. In the open position, the housing and the powder feeder are in a spatial relationship that allows the housing dispense the unit dose into the user's mouth without impediment due to the presence of the powder feeder. With the in order to reduce the steps involved in dispensing the medication, the folding action from the open position to the closed position, or vice versa, it can trigger a step in the dispensing process. For example, opening the device could trigger the filling of the opening and / or movement of the moving part from the second position to the first position. Moreover, the opening of the device could trigger the filling of the opening, the movement of the moving part from the second position to the first position during the initial opening, and the movement of the moving part back to the first position for dispensing, during the end of the opening action, when the dispensing Subsequent is not prevented by the powder feeder. He Powder fed can comprise any mechanism to measure dust, including any of the deposit systems described above, for example, the powder feeder can comprising a housing (228) forming an internal reservoir (229) to contain multiple doses of the medicine in powder form (230), a hole (231) in communication with the tank and an outlet of distribution (232) in communication with the gap, in which the powder feeder is able to provide a unit dose of the medication from the warehouse to the distribution outlet. In a embodiment, the powder feeder further comprises a piece slide (233) inside the tank and the hole that has a filling cavity (234) arranged therein, having the piece Sliding a first position (235) with the filling cavity located in the tank and a second position (236) with the cavity of filling located in the hollow and in communication with the output of distribution, in which after the movement of the sliding piece from the first position to the second position, a unit dose of the drug from the powder feeder to the filling opening of the moving part.

Another embodiment of the invention, as shown by Fig. 23, is directed to a device for depositing a medication on a patient's tongue, which comprises a housing (231) forming a reservoir (232) and a recess (233) in communication with the tank, the housing having an opening (234) which connects the hole with the outside of the housing, the housing adapted to fit inside the oral cavity of a human patient with the opening facing the tongue of the patient; a moving part (235) that has a filling opening (236) capable of containing a dose of medication, the piece being mobile adjusted inside the gap in a first position (b) in the that the filling opening is in communication with the tank and being able to be filled with the dose, the moving part being capable of being placed in a second position (d) with the opening filling in communication with the opening of the housing in which The dose of medication is discharged onto the patient's tongue. In certain embodiments, the moving part is slidable. horizontally from the first position to the second position or is rotatable inside the elongated housing and rotates from the first position to the second position. The device can understand also a locking mechanism (237) to maintain the position of the filling opening in a position between the first and the second position (c). Preferably, the device comprises a mechanism, for example, a spring (238), to place the part mobile in the second position after the release of the mechanism blocking. Preferably, the upper tapered end is of long enough to allow the dose to be deposited on the back of the patient's tongue and have a removable cap (239).

The systems and the device of the present invention should contain the powder in order to prevent the contamination from the outside environment as well as ensuring closure or prevent the loss and disposal of dust. This can be done. by elastomeric sealing gaskets that can provide a closure between the tank and the other components to prevent leakage or dust leakage from the tank. Moreover, this can be done. perform by predisposing the components with, for example, a screw, in order to provide a friction adjustment airtight between the components that contain the medicine.

Another aspect of the invention is directed to new nozzles that help coordinate unit dose within The oral cavity

In certain embodiments, the nozzle protrudes initially of the device similar to a nozzle Traditional in a standard inhaler. However, after initial protrusion, the nozzle angles down in order to direct the unit dose on the user's tongue, as shown in Fig. 24. This is to ensure that as close to 100% as if possible the unit dose is subsequently absorbed by the gastrointestinal tract and not inhaled in the pulmonary system. The angled nozzle may have a marked angle (Fig. 24) or may be curved, as shown in Fig. 25.

In another embodiment, rather than having the angled or curved nozzle, the nozzle can be straight, but can protrude from the device at an angle, when the device is in an upright position (Fig. 26), in order to direct the dose unity over the language and also reduce any deviation in the angled or curved nozzle nozzle that can have as result that some medication is retained and not distributed by the system.

Another new feature of the mouthpiece of the present invention is having a flared mouthpiece that reduces the speed of multiparticles and prevents spreading and dispersion of the dose that can lead to pulmonary infiltration. In the prior art, narrowed or Venturi-style pieces resulted in increased speed during distribution, which is beneficial for pulmonary inhalation. By virtue of the flared nozzle of the present invention, the speed of the multiparticles is not increased, thereby increasing the percentage of drug deposited gastrointestinally. As shown in Fig. 27, the flared nozzle can be tapered, (270), in which the diameter of the nozzle outlet (271) is larger than the internal inlet (272) in which the Unit dose enters the mouthpiece. In preferred embodiments, the outlet diameter is 25%, 50% or 100% larger than the inlet diameter of the nozzle. However, these percentages do not mean that they are
limiting

In other embodiments, as shown in the Fig. 28, the nozzle can be rectangular (281), with the part upper (282) and lower (283) horizontals that are longer than the sides (284) in order to fit inside the mouth of a patient. Similar to the conical nozzle, the outlet of the opening (285) will be larger than the entrance opening (286). By For example, the surface area of the outlet opening can be 25%, 50% or 100% larger than the entrance opening.

In other embodiments with a nozzle rectangular style, as shown in Fig. 29, the ledge Out of the nozzle (291) may be similar to a fan. In such embodiment, the side walls (292) of the nozzle are extend outward from the beginning of the nozzle (293) as nulls, for example, 15 degrees, which go in the opposite direction between Yes to provide the flight. When the walls reach the desired distance, the top and bottom of the nozzle (294) are convex on their own edges (295) in order of providing the fan-like appearance.

In certain embodiments of the invention, the medication distribution devices known in the technique, for example, the powder inhaler technique, can be modify / adapt in order to have the capacity and possibility of triggering a unit dose of particles that have a size appropriate for gastrointestinal distribution with minimal inhalation in the pulmonary system Such devices are described in the previously mentioned documents WO 94/04133, United States Patent No. 4,590,206 and WO 93/25198. Other devices are described then:

One such device is known as the Bespak device described in PCT publication WO 92/00771, available from Innovata Biomed Limited. The device described in she includes a storage camera to store a Powdered medicine to be administered and a piece of measure which has measuring cups in which doses are placed individual drug powder. Air is inhaled through a  aeration passage at one end of the device and is directed at contact with the measuring cup that has been filled with the Powdered medicine The measuring cup is oriented towards open up to face the air flow and to make it is possible that the dust is released from the bowl. Behind the inhalation, the dose is mixed with the air flow and continues to through the mouthpiece to be inhaled. The measuring cups in the measurement piece are arranged in a conical trunk wall of so that each measuring cup is positioned to be open up and facing the flow of air during inhalation. The measuring piece rotates so that the measuring cups move between a position in which the bowl receives a dose of powder medicine from the storage chamber to a position in which the bowl is exposed to air flow. TO as a bowl is exposed to air flow, another bowl it aligns with the storage chamber and is being filled with powder. After the dose is blown from the bowl of measurement, and after the subsequent rotation of the measurement piece, the bowl is rinsed and cleaned by a cleaning element to remove any non-dispersed powder and then dried by means of a moisture absorbing material.

Other device for powder distribution for inhalation is described in US Pat. No. 2,587,215 (Priestly). Priestly describes an inhaler that has a storage chamber that contains a powder medicine, a mixing chamber and means to move a set of doses of medication from the storage chamber to the storage chamber mixture. The dose is mixed with air in the mixing chamber and inhale through the mouthpiece.

Still another appropriate inhalation device to distribute powder inhalation medication is described in US Patent No. 4,274,403 (Struve). Struve describes an inhaler to nasally administer a medication in powder, which includes a storage medium to contain a amount of medicine in it. The storage medium includes a feed hole through which the Powdered medicine from the storage medium. He device also includes a dispensing head coupled operatively to the storage medium to dispense the powder more nasally. The dispensing head of the Struve inhaler includes a mouthpiece, a body part, a dispensing cylinder and a purge medium. The mouthpiece is shaped to be received in the nasal passage of the user. The nozzle includes a dispensing passage to dispense the dose in the nasal cavity of the patient. The body portion is located adjacent to the nozzle and has a cross hole in it. He cross drill operatively connects the passage of dispensing at the nozzle with the feed hole that leads to the medication storage medium. The hole of feeding and dispensing passage are diverted transversely in relation to each other at the points where they enter in the cross drill.

The dispensing cylinder includes a chamber of measure. The measuring chamber can be selectively aligned or with the feeding hole or with the dispensing passage. The dispensing cylinder is slidably received in the cross drill for movement between a first position transverse in which the measuring chamber is aligned with the feed hole and a second transverse position in the that the measuring chamber is aligned with the dispensing passage. In its first position, the measuring chamber can be filled with a loading of the powdered medicine when the inhaler is handled. In the second position, place the powder drug load in the dispensing passage for inhalation by the user. The middle of purge is formed as part of the dispensing cylinder and is capable of download the measuring chamber to the atmosphere only in the second cylinder position, that is, when the powder is arranged in the device so that it can be inhaled by the user.

Another inhaler device is described in the U.S. Patent No. 4,524,769 (Wetterlin). Wetterlin describes a dosage inhaler to administer a substance pharmacologically active micronized to a patient. The inhaler includes a gas conduit means through which gas is passed to transport the micronized substance to be administered. The inhaler further includes a membrane that has a plurality of pre-selected perforated portions, each portion being adapted to contain and dispense a reproducible unit dose less than 50 mg of said active substance, in the form of dry powder. Dust particles have a particle size less than 5 micrometers The membrane is mobilely connected to the medium of gas conduit so that one of the preselected portions it can be placed inside the gas conduit means so that the substance contained in the preselected portion may be dispensed The remaining preselected portion may be in a external position to said gas conduit means to receive said active substance. The membrane is mobile by a plurality of positions whereby each preselected portion of the membrane can be placed successively inside the gas conduit to dispense the unit dose of the active substance contained in she. Each preselected portion from which the active substance can be moved to said external position to Receive active substance.

Great Britain Patent Application No. 2,041,763 describes an inhaler that has a camera dust storage and a rotating measurement piece that has dosing holes that open towards the chamber of storage in one position and open towards the mixing chamber in another position. After the rotation of the measuring piece, the powder is taken from the storage chamber to the camera Mix to be inhaled.

EP 0 079 478 describes an inhaler which has a storage chamber, air passage for inhalation and a rotating distribution part that has a cavity formed in it. The distribution part is rotated from a position in which the cavity receives dust from the chamber of storage to another position where dust falls from the gravity cavity in a collector placed in the air passage

US Patent No. 4,860,740 (Kirk et al .) Describes an inhaler that has a rotating measurement piece with voids formed therein. These holes contain a powder medicine. After rotation of the measuring piece, one of the gaps is exposed to the air inhalation passage to be drawn into the air stream and inhaled.

The Easyhaler?, Described in the publication PCT WO 92/09322 available from Boehringer Ingelheim is illustrative of another appropriate device that can be adapted / modified to distribute the formulations of the present invention. He device includes a supply of a medical substance sprayed and a "dosing medium", which is a cylinder swivel that has five uniform gaps arranged around the periphery of the cylinder. The cylinder is rotated so that a gap aligns with the medication supply and is filled by a quantity of the medication while another gap is aligned with an air channel connected to the nozzle. The filled hole is rotated then to another position on the direct path of an air flow of inhalation. The dose is preset by the cupped portion of the Rotating dosing medium and is cleaned by air flow Direct through the inhalation chamber. To operate the device, the rotating dosing means is rotated so that a complete dosing chamber is rotated (which has already been filled after previous use) in alignment with the air channel that It leads to the nozzle. After inhalation by the user, the air it is sucked through openings and nozzles directly to the chamber of dosage. The air flow washes the dosing chamber causing the medication to be carried with the air in the direction of inhalation through the mouthpiece. The axis of the air channel is arranged at an angle to the axis of the dosing medium of between 70 degrees and 110 degrees, but preferably 90 degrees (perpendicular).

U.S. Patent No. 5,176,132 describes a device for administration to the lung by inhalation of a medicine in powder form. The device includes a mouthpiece, a medication reservoir that communicates with said nozzle, and measuring means for dispensing a dose of medication from the deposit. The tank contains a body compacted powder medicine that includes an active ingredient which has a particle size from 1 to 10 µm when It is in the form of loose powder. The measuring medium includes a Rotating helical blade to lower the compacted body. So, when activated, the helical blade rae the medication in compacted powder in particles capable of being inhaled in the tract Respiratory of a patient.

International Patent Applications PCT / EP93 / 01157 and PCT / EP93 / 01158 (assigned to GGU) are directed to a inhalation device and an annular tablet, respectively. The GGU device includes a deposit body  of medicine located in a mouthpiece. The body forms the principle of an inhalation tube through which the medicine. The medicine is in compacted and annular form (of ring). In use, a front milling cutter rotates generating drug particles. After inhalation, the air flows to through the air inlet openings on the deck and in the cutting edge area of the front milling cutter. Together with the depressions located between the cutting edges, the inlet openings and depressions form an air channel that leads to the mouthpiece, through which the particles are inhaled of medication.

The amount of each dose is determined by the amount of rotations of the front cutter cutter. A pier press the inhalation tube and therefore the medication body towards the front milling cutter. In the operation, a winding button to load the spring. Pressing the mechanism trigger, the spring is released by rotating the part higher than the front cutter cutter is connected.

Other representative inhalers for medications are those described in, for example, US Patents Nos. 3,157,179, 3,178,748, 3,183,907, 3,356,088, 3,361,306, 3,456,644, 3,456,646, 3,565,070 , 3,656,070, 3,636,949, 3,658,059, 3,732,864, 3,789,843, 3,814,297, 3,991,761, 3,826,413, 4,206,758, 4,414,972, 4,484,577,
4,534,345, 4,592,348, 4,817,822, 4,484,577, 4,926,852, 4,790,305, 4,210,155, 4,852,561, 4,644,107, 4,677,975,
4,803,978, 4,934,358, 4,955,371, 5,020,527, 5,048,514, 5,060,643, 5,224,471, 5,250,287, 5,284,133 and 5,351,683. Representative nasal-pharyngeal inhalers for large mammals, such as a horse, is the one described in US Patent No. 5,062,423.

Representative devices for handling powder forms of medicines are shown and described in several United States Patents, including United States Patents Nos. 6,142,146, 6,116,238, 6,073,818, 6,071,498, 6,065,471, 6,029,663 , 6,006,747, 5,934,273, 5,875,776, 5,871,010, 5,785,049, 5,577,497, 5,694,920, 5,642,728,
5,568,807, 5,546,932, 5,524,613, 5,476,093, 5,447,151, 5,383,850, 5,372,128, 5,301,666, 5,287,850, 5,263,475,
5,042,472, 4,889,114, 4,860,740, 4,846,168, 4,338,931, 5,458,1351, 5,388,572, 5,349,947, 3,507,277, 3,518,992, 3,635,219, 3,831,606, 3,948. 264, 3,971,377 and 4,147,166. Dry powder inhalers include dose inhalers, for example, the single dose inhaler known by the registered trademark Monohaler®, and multiple dose inhalers, for example, a breathing powder dry, multi-dose inhaler, such as the inhaler known by the registered trademark Turbohaler®. Many of these prior art devices use powdered medicine contained in a gelatin capsule or vial with a separate dose contained in each capsule or vial. For example, US Patent Nos. 3,507,277, 3,518,992, 3,635,219, 3,795,244 and 3,807,400 describe inhalation devices that have means for piercing a capsule containing a powdered medicament, which in Inhalation is aspirated from the perforated capsule and into the user's mouth. In US Patent No. 2,517,482 a device is described having a capsule containing powder placed in a lower chamber before inhalation, where it is perforated by manual depression of a piercing tip by the user. After perforation, the inhalation is started and the capsule is taken to an upper chamber of the device where it moves around in all directions to produce a dispensing of dust through the perforated holes and in the inhaled air stream. A well-known dry powder inhaler, the Diskhaler, described in US Patent No. 4,627,432, uses individual medication doses sealed inside ampoules or in a blister disc. A plunger pierces the blisters to release each dose. The disc is advanced by a button with each successive dose. The Spiros inhaler, described in US Patent Application Serial No. 08 / 681,103, is a dry powder inhaler that also uses a blister disc. Another inhaler described in PCT Application No. PCT / US93 / 09751 contains individual doses of medication stored within a plurality of openings in a cartridge containing the medicament. The cartridge is manually advanced for successive doses by rotating the cartridge containing the medication. U.S. Patent Nos. 5,327,883 and 5,577,497 describe an inhaler having a rotating impeller.

Known devices for distributing aerosol medication for inhalation by a patient include metered dose inhalers that are operated manually and operated by breathing. Some examples of devices for distributing aerosol medication for inhalation are described in U.S. Patent Nos. 5,960,792, 5,848,587, 5,738,087, 5,666,948, 5,617,844, 5,505,194, 5,394,866, 5,290. 539, 5,165,391, 5,027,806, 4,955,371, 4,852,461, 4,790,305, 4,509,515, 5,954,047, 5,755,218, 5,724,986, 5,622,162, 5,544,647, 5,505,194,
5,392,768, 5,304,125, 4,852,561, 3,187,748, 3,565,070, 3,814,297, 3,826,413, 4,592,348, 4,648,393, 4,803,978 and 4,896,832, a product available from 3M Healthcare known as Aerosol Sheathed Actuator and Cap; and a product available from Riker Laboratories known as Autohaler.

Some examples of actuator devices Aerosol fixed construction in one piece are described in U.S. Patents Nos. 3,918,451, 3,991,761, 4,011,864, 4,069,819, 4,227,522, 4,265,236, 4,454,877, 4,576,157, 4,648,393, 4,860,740, 5,002,048, 5,012,804, 5,115,803, 5,134,993, 5,161,524 and 5,178,138.

Devices that are articulated and that can be fold or pick up telescopically for proper transportation in a pocket or purse are described in the United States Patents United numbers 3,739,950, 3,788,316, 3,927,806, 3,994,421, 4,130,116, 4,292,966, 4,509,515, 4,637,528 and 4,641,644.

Breath-activated inhalers they differ from pressurized aerosol inhalers in that breath-activated inhalers are activated by the user inhalation so that the medication is reliably aspirated to the distal regions of the lung. Inhalers typical breathing-activated are described in the U.S. Patents Nos. 6,102,036, 5,483,954, 4,846,168 and 4,524,769. Other systems also include a means of operating the Medication release by initiation of inhalation. Such devices have been described in the US Pat. United numbers 4,664,107, 4,803,978 and 4,739,754.

Some inhalers powered by the breathing and disposables are described in WO 89/01348 and United States Patent No. 4,265,236. Others disposable inhalers are described in the United States Patents United 6,102,035, 6,062,213, 5,660,169, 5,533,505 and 4,955,371.

Other more recent improvements in inhalers are described in U.S. Patent Nos. 6,149,892, 6,143,277, 6,131,566, 6,116,234, 6,062,213, 6,083,514, 6,074,668 and 5,878,917.

Claims (58)

1. A device for oral administration of a therapeutic agent for gastrointestinal deposition or absorption sublingual or buccal, comprising a housing and an actuator and multiple doses of multiparticles comprising particles of medication, distributing said device after actuation a unit dose of said multiparticles, the unit dose from the device substantially by force gravitational and with an air flow of less than 20 liters / minute, in which said medicament particles have an average diameter greater than 10 µm to about 1 mm, so that a dose Effective of such medication cannot be distributed to the lung inferior of a human patient. 2. A device according to claim 1, wherein said distribution is administered in vivo said unit dose in the oral cavity of a patient. 3. A device according to claim 1, wherein said distribution is dispensing said unit dose ex vivo in an intermediate receptacle. 4. A device according to claim 1, in which said unit dose is in the form of a discrete unit. 5. A device according to any of the claims 1, 2 or 4, wherein said device administers said unit dose on the tongue of said patient. 6. A device according to any of the claims 1-5, wherein said particles of medication have an average diameter greater than about 50 \ mum. 7. A device according to any of the claims 1-6, wherein said multiparticles further comprise a pharmaceutically excipient acceptable. 8. A device of claim 7, in the that said excipient is coated with said medicament. 9. A device of claim 7, in the that said medicament is coated with said excipient. 10. A device of claim 7, in the that the medicine and the excipient are a mixture of powders. 11. A device of claim 7, in the that said excipient comprises a masking agent of the taste. 12. A device of claim 7, in the that said excipient comprises a sweetening agent, agent flavoring or combination thereof. 13. A device of claim 7, in the that said excipient comprises a salivary stimulant, an agent effervescent or a combination thereof. 14. A device of claim 7, in the that said excipient comprises a release material controlled. 15. A device of claim 14, in that said excipient is less than about 20% by weight of said multiparticles. 16. A device according to any of the claims 1-15, wherein said dose Multiple are contained in a warehouse. 17. A device of claim 16, which It also includes a measuring component for measuring a dose unit of said medication from the deposit in the actuation of said device. 18. A device of the claims 1-17, wherein said device comprises a drum that has an inner cavity arranged in it to contain said multiparticles, said drum having a coating exterior, a rotating interior lining arranged immediately inside the outer lining and a band of stationary retention located immediately within a portion of said inner lining; having said coating outside a dispensing hole at a point below the retention band for dispensing said unit dose; having said rotating inner liner a filling hole arranged in it and having a first position where said filling hole is not adjacent to said retention band to allow a unit dose of these to be filled in it multiparticles; said rotating interior lining having a second position where said filling hole is adjacent to said retention band and in communication with said hole outside, in which said unit dose is distributed from the deposit to said dispensing hole when the coating interior moves from said first position to said second position in the drive and the unit dose is expelled from the device.

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19. A device of the claims 1-17, wherein said device comprises a deposit to contain said multiparticles, having said deposit an exit hole in it; a rotating piece out of said deposit having an external cavity in communication with said outlet opening when said rotating part is in a first position to allow a unit dose to be filled in it of said multiparticles; immediately covering a housing of stationary retention said rotating part, said housing having  retaining a dispensing hole disposed therein; said rotating part having a second position in which said external cavity of said rotating part is in communication with said dispensing orifice, wherein said unit dose is distributed from the reservoir to said dispensing hole when the rotating part moves from said first position to said second position in the drive and the unit dose is expelled from the device. 20. A device of the claims 1-17, wherein said device comprises a deposit to contain said multiparticles, having said deposit an exit hole in it; a rotating piece out of said deposit having a plurality of external cavities; a stationary retention housing that immediately covers said rotating part, said retention housing having an orifice of dispensation arranged in it; said rotating part being in position in which an external cavity is in communication with said outlet opening to be filled with a unit dose of said multiparticles and an external cavity is in communication with said dispensing hole; said piece being rotatable swivel to advance each cavity to the exact position of the next adjacent cavity in the drive, in which a unit dose of said multiparticles is distributed from said dispensing hole when a cavity containing said unit dose is advanced to be in communication with said dispensing hole. 21. A device of the claims 1-17, wherein said device comprises a deposit to contain said multiparticles, having said deposit an exit hole in it, a mobile plate that has a filling hole disposed therein, said movable plate having a first position in which said filling hole is in communication with said outlet port of said tank; a stationary retention plate immediately under said plate mobile to form a filling cavity with said orifice of filled to be filled with a multi-particle unit dose when said movable plate is in said first position, having said stationary retention plate a dispensing hole; said moving plate having a second position in which said filling hole is in communication with said opening of dispensing and said unit dose is dispensed from said device, wherein said movable plate moves from said first position to said second position in the drive 22. A device according to claim 21, wherein said device has a stationary top plate immediately on said movable plate that has a hole in it in communication with said orifice of the reservoir and said orifice of fill. 23. A device of the claims 1-22, wherein said device comprises a nozzle. 24. A device of claim 23, in which said nozzle is of sufficient length to minimize the moisture exposure of multiparticles from outside the device. 25. A device of claim 23 or 24, wherein said device further comprises a cover for the nozzle to minimize moisture exposure of multiparticles from outside the device. 26. A device of the claims 1-25, which further comprises a desiccant for minimize exposure to moisture of multiparticles from The outside of the device. 27. A device of the claims 1-26, in which said doses are measured individually before said drive. 28. A device of claim 27, in the one that the dose measures me in a capsule. 29. A device of claim 27, which It also includes ampoules on a substrate base, containing each ampoule said unit dose measured individually, covering said blisters by means of a seal. 30. A device of claim 29, in which said blisters are linearly aligned in the form of a band. 31. A device of claim 30, in which said band is in the form of a roll. 32. A device of the claims 1-5, in which said housing has a cavity inside formed in it to contain multiple doses of said multiparticles, said housing having a tapered upper end with an opening in it and a tapered bottom end; and that it also comprises a lifting rod fitted in a first position inside the tapered lower end of the housing that is movable to a second position inside the tapered upper end of the housing, said lifting rod comprising a cylinder elongated with an upper end and an inner push rod inside the elongated cylinder that ends at a point below the upper end of the cylinder to form a filling cavity when the lifting rod is in the first position, being said inner push rod movable to end at one point above the upper end of the cylinder when the rod lift is in the second position; in which, when the device is vertical in the first position, said cavity of filling is filled with a unit dose of said multiparticles, and when the lift rod moves to the second position after the drive, the inner push rod moves to a point above the upper end of the cylinder and the unit dose is distributed from the housing. 33. A device according to claim 32, in which the placement of the inner push rod in the elongated cylinder in the first position is adjustable in order to vary the volume of the filling cavity and individualize the dose of said medication. 34. A device according to any of the claims 1-5, wherein said housing has an inner cavity, said housing having an opening that connect the inner cavity with the outside of said housing, said housing being adapted to fit inside the cavity oral of a human patient with the opening facing the tongue of said patient; and which also comprises a movable piece inside of said inner cavity, said movable part having a filling opening capable of containing a dose of medication, said filling opening being closed by said housing when said movable piece is in a first position, being able said movable part to be placed in a second position in the that said filling opening is in communication with said opening of the housing to load said medicine in said opening or to distribute said medication. 35. A device according to claim 34, wherein said movable piece is horizontally slidable from said first position to said second position; or rotatable within said elongated housing and rotates from said first position to said second position. 36. A device according to claims 34 or 35, further comprising a powder feeder coupled to said opening of said housing to deposit a unit dose of medicament in said opening when said movable piece is in the second position, said powder feeder being movable from said opening of said housing in order to allow the deposit of said dose on the tongue of said patient. 37. A device of claims 1-5, wherein said casing has a reservoir and a recess in communication with said reservoir, said casing having an opening that connects the recess to the outside of said casing, said casing being adapted to fit inside the oral cavity of a human patient with the opening facing the tongue of said patient; a movable part that has a filling opening capable of containing a dose of medicament, said movable part being embedded within said recess in a first position in which said filling opening is in communication with said reservoir and is capable of being filled with said dose, said movable part being able to be placed in a second position after actuation with said filling opening in communication with said opening of the housing in which the dose of
medicine. 38. A device according to claim 37, wherein said movable piece is horizontally slidable from said first position to said second position or rotatable within of said elongated housing and rotates from said first position to said second position. 39. A device according to claim 1, comprising a housing to contain multiple doses of multiparticles comprising drug particles, having said housing an opening to distribute a unit dose of said multiparticles; an operable measurement component between a first position in which you receive a unit dose from said housing and a second position in which it distributes said dose unit to said opening in said housing; being distributed said unit dose from said measurement component outside the device through said opening of said housing with a air flow less than about 20 liters / min. 40. A device according to claim 39, wherein said device does not include a propellant to facilitate The unit dose distribution. 41. A device according to claim 1, in which multiparticles comprise a plurality of particles that flow freely, not compressed, that comprise a medicine and a pharmaceutically acceptable excipient, having said medicament particles an average diameter greater than 10 µm up to about 1 mm, said particles comprising at least About 80% of medication. 42. A device of claim 41, in which said particles comprise at least 90% of medicine. 43. A device according to claim 41 or 42, in which the multiparticles further comprise an agent facilitator that improves the oral administrability of said dose unity. 44. A device according to claim 43, wherein said facilitating agent is an enhancer of the absorbability, a texture modifier, an agent flavor masker, a sweetener, a flavoring, a salivary stimulator, an effervescent compound or its combinations 45. A device of claim 44, in which said salivary stimulator is citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, their acid anhydrides, their salts or combinations. 46. A device of the claims 42-45, wherein said excipient comprises a release material maintained. 47. A device of the claims 42-46, wherein said particles are divisible into unit doses containing a therapeutically effective amount of said medication, wherein the amount of said medication is about 1 mg to about 500 mg. 48. A device of the claims 42-46, wherein said medicament particles they have an average diameter greater than about 50 µm. 49. A device of the claims 42-48, in which 80% of the particles of medicament have a diameter greater than 10 µm to about 1 mm 50. A device of the claims 42-49, in which 80% of the particles of medicament have a diameter greater than about 50 µm up to about 1 mm. 51. A device according to claim 1, comprising a housing to contain multiple unit dose of a drug in the form of multiparticles; having said housing a nozzle for distributing a unit dose of said multiparticles in the oral cavity of a patient; means for separating a unit dose of said multiparticles from said housing and transporting said unit dose to said nozzle, said nozzle a receiving end of the medicament connected to said means and a drug distribution end through which it distributes said unit dose outside the device, being said nozzle placed in said device so that the medication expelled through said nozzle can be deposited in the oral cavity of a patient substantially without deposition of said particles in the lungs of said patient. 52. A device according to claim 1, to distribute multiple unit doses of a medication in form multi-particle, comprising a housing to contain multiple unit doses of a drug in the form of multiparticles; said housing having a nozzle to distribute a unit dose of said multiparticles in the oral cavity of a patient; a meter to separate a unit dose from said multiparticles of said housing and transporting said unit dose to said nozzle, said nozzle having a receiving end of the medicine connected to said measuring device and an end of distribution of the medication through which said medication is distributed unit dose outside the device, said nozzle being placed in said device so that the medication expelled through of said nozzle can be deposited in the oral cavity of a patient substantially without deposition of said particles in the lungs of said patient. 53. A device of the claims 1-52, which distributes greater than 80%, preferably greater than about 90%, and preferably about 100% of the unit dose in a downward direction at about 45 degrees up to about 135 degrees, based on a baseline device independent vertical. 54. A device according to claim 1, which further comprises a mouthpiece for administering a medication in the form of multiparticles in the oral cavity of a patient, said nozzle having an outlet to distribute said multiparticles and an entry to receive said multiparticles, the improvement being that the nozzle protrudes downward from the medication distribution device at an angle greater than around 15 degrees measured from a horizontal baseline when the medication device is upright, in order to direct the multiparticles on the language of said patient. 55. A device according to claim 54, in which the nozzle outlet looks down to administer  said multiparticles on the tongue of said patient. 56. A device according to claim 54 or 55, in which the nozzle is conical in shape and has an outlet that It has a larger diameter than an inlet where multiparticles enter said nozzle. 57. A device according to claim 56, in which the diameter of the nozzle outlet is 25%, 50% or 100% larger than the diameter of the entrance. 58. A device of claims 54 a 55, the nozzle having upper and lower walls that are convex at its outer edges.